Project Summary/Abstract The research in our laboratory centers on understanding signaling mechanisms in cell death and survival, inflammation, immune responses and pathogen infection, using I?B kinase (IKK) signaling network as a molecular probe to explore potential intervention of the signaling mechanisms for prevention and treatment of inflammatory and infectious diseases. Our goals for the next five years are: 1) understanding the molecular mechanism that controls TNF? cytotoxicity in inflammatory and infectious diseases. Previously, we reported that TNF?-induced apoptosis is suppressed by IKK-mediated inhibition of the pro- apoptotic BCL-2 family member BH3-only protein BAD in addition to activation of NF-?B under physiological or developmental conditions. Our unpublished results demonstrated that TNF? cytotoxicity in severe sepsis is mediated by massive BAD release from cytoskeleton despite concurrent activation of IKK and NF-?B. We plan to determine the underlying mechanism and its potential applications in other inflammatory and infectious diseases in which TNF? cytotoxicity plays a crucial role in disease pathologies; 2) computational modeling TNF? cytotoxicity. Our unpublished results demonstrated that IKK signaling network suppresses TNF?-induced apoptosis through coherent feedforward regulation. We plan to use computational modeling to explore how fundamental mathematics and physical sciences concepts have been applied to regulate TNF? cytotoxicity by IKK signaling network at systems level, thereby putting forward novel hypotheses beyond the empirical data for further testing; and 3) novel regulatory mechanism of non-canonical IKK-NF-?B network. Our unpublished results demonstrated that the transcription factor Miz1 is required for activation of non-canonical NF-?B by lymphotoxin (LT) and other stimuli independently of its transcriptional activity and Miz1-deficient mice display impaired clearance of Citrobactor rodentium infections. We plan to study the underlying mechanism and its role in mucosal immune responses against bacterial infection. The overall vision of the research program in our laboratory is to provide novel strategies and identify molecular targets for prevention and treatment of inflammatory and infectious human diseases.